Taxol-induced unfolded protein response activation in breast cancer cells exposed to hypoxia: ATF4 activation regulates autophagy and inhibits apoptosis

2015 ◽  
Vol 62 ◽  
pp. 1-14 ◽  
Author(s):  
Annick Notte ◽  
Magali Rebucci ◽  
Maude Fransolet ◽  
Edith Roegiers ◽  
Marie Genin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Unfolded Protein ◽  
Protein Response ◽  
Response Activation

TXNIP links anticipatory unfolded protein response to estrogen reprogramming glucose metabolism in breast cancer cells

Endocrinology ◽  
2021 ◽  
Author(s):  
Yuanzhong Wang ◽  
Shiuan Chen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Breast Cancer Cells ◽  
Unfolded Protein ◽  
Protein Response

Abstract Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To adapt the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory unfolded protein response (UPR) and subsequently repressing TXNIP expression. By using two widely used ER+ breast cancer cell lines MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Together, our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells, and links anticipatory UPR to estrogen reprogramming glucose metabolism.

scholarly journals Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response

2013 ◽  
Vol 15 (1) ◽  
Author(s):  
Anika Nagelkerke ◽  
Johan Bussink ◽  
Hilda Mujcic ◽  
Bradly G Wouters ◽  
Steffi Lehmann ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

A synthetic chalcone, 2'-hydroxy-2,3,5'-trimethoxychalcone triggers unfolded protein response-mediated apoptosis in breast cancer cells

2016 ◽  
Vol 372 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Da Hyun Lee ◽  
You Jung Jung ◽  
Dongsoo Koh ◽  
Yoongho Lim ◽  
Young Han Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals OR05-05 Lethal ERα-Dependent Hyperactivation of the Unfolded Protein Response Induces Complete Regression Without Recurrence of Primary and Metastatic Breast Cancer

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Darjan Duraki ◽  
Matthew W Boudreau ◽  
Lawrence Wang ◽  
Chengjian Mao ◽  
Bingtao Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Metastatic Breast ◽  
Complete Regression ◽  
Necrotic Cell ◽  
Unfolded Protein ◽  
Protein Response ◽  
Positive Breast Cancer

Abstract Metastatic estrogen receptor α (ERα) positive breast cancer is presently incurable and most patients die within 7 years. From a medicinal chemistry program, we identified a novel small molecule that acts through ERα to kill breast cancer cells and often induces complete regression without recurrence of large, therapy-resistant primary breast tumors and of lung, bone, and liver metastases. To target metastatic ERα positive breast cancer, we exploited our finding that estrogen-ERα activates an extranuclear tumor-protective, signaling pathway, the anticipatory unfolded protein response (UPR). We repurposed this tumor protective pathway by targeting it with the small molecule, ErSO. ErSO kills cancer cells by acting non-competitively through ERα to induce lethal hyperactivation of the anticipatory UPR, triggering rapid necrotic cell death. Using luciferase to image primary tumors and metastases containing lethal ERαD538G and ERαY537S mutations seen in metastatic breast cancer, oral and injected ErSO exhibited unprecedented antitumor activity. In mouse xenografts bearing large breast tumors, oral and injected ErSO induced complete regression (>115,000 fold mean regression) in about 45% of mice (18/39). Although durable response for 4-6 months without additional treatment was common, tumors that did recur remained fully sensitive to ErSO re-treatment. Consistent with the essential nature of the UPR pathway targeted by ErSO, in more than 100 tumor-bearing mice, we have never seen an ErSO-resistant tumor. In just 7 days, oral ErSO induced complete regression of most lung, bone, and liver metastases. ErSO is well-tolerated in mice and blood-brain-barrier penetrant. Injected ErSO induced profound regression of challenging brain tumors. On average, ErSO-treated tumors were >180-fold smaller than vehicle-treated tumors. These xenograft studies used human cancer cells in mice that lack a functional immune system and therefore did not exploit the known ability of inducers of necrotic cell death to activate immune cells and induce immunogenic cell death. Notably, medium from breast cancer cells killed by ErSO contained high levels of immune cell activators, robustly activated mouse and human macrophages and increased macrophage migration. Moreover, use of ErSO is not limited to breast cancer. ErSO rapidly kills ERα positive ovarian and endometrial cancer cells that do not require estrogen for growth. ErSO’s potent activity against advanced primary and metastatic ERα-positive breast cancers represents a paradigm shift in leveraging ERα for anticancer efficacy.

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